Psychiatric medications, science, marketing, psychiatry in general, and occasionally clinical psychology. Questioning the role of key opinion leaders and the use of "science" to promote commercial ends rather than the needs of people with mental health concerns.

Monday, April 28, 2008

A bombshell has just appeared in the International Journal of Risk & Safety in Medicine. The subject of the paper is Paxil study 329, which examined the effects of the antidepressant paroxetine in adolescents. The study findings were published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001. These new findings show that I was wrong about Paxil Study 329. You know, the one that I said overstated the efficacy of Paxil and understated its risks. The one that I claimed was ghostwritten. Turns out that due to legal action, several documents were made available that shed more light on the study. The authors (Jureidini, McHenry, and Mansfield) of the new investigation have a few enlightening points. Let's look at the claims and you can then see how wrong I was, for which I sincerely apologize. The story is actually worse than I had imagined. Here's what I said then:

Article [quote from the study publication]: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo.On four of eight measures, paroxetine was superior to placebo.Note, however, that its superiority was always by a small to moderate (at best) margin.On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

I went on to bemoan how the authors took differences either based on arbitrary cutoff scores or from measures that assessed something other than depression to make illegitimate claims that paroxetine was effective. Based upon newly available data from the study, here's what happened.

The protocol for the study (i.e., the document laying out what was going to happen in the study) called for eight outcome measurements. To quote Jureidini et al: "There was no significant difference between the paroxetine and placebo groups on any of the eight pre-specified outcome measures." So I was wrong. Paxil was not better on 4 of 8 measures -- it was better on ZERO of eight measures. My sincerest apologies.

Another quote from Jureidini and friends: "Overall four of the eight negative outcome measures specified in the protocol were replaced with four positive ones, many other negative measures having been tested and rejected along the way."

Let's break this thing down for a minute. The authors planned to look eight different ways for Paxil to beat placebo. They went zero for eight. So, rather than declaring defeat, the authors then went digging to find some way in which Paxil was better than a placebo. Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

How About Safety?

I was incensed about the coverage of safety, particularly the magical writing that stated that a placebo can make you suicidal, but Paxil could not. I wrote:

It gets even more bizarre.Remember those 10 people who had serious adverse psychiatric events while taking paroxetine?Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine.Interestingly, the one person who became “labile” [i.e., suicidal] on placebo – that event was attributed to placebo.In this magical study, a drug cannot make you suicidal but a placebo can.In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring.

Turns out I missed a couple things. Based on looking at an internal document and doing some calculations, Jureidini et al. found that serious adverse events were significantly more likely to occur in patients taking paroxetine (12%) vs. placebo (2%). Likewise, adverse events requiring hospitalization were significantly disadvantageous to paroxetine (6.5% vs. 0%). Severe nervous system side effects -- same story (18% vs. 4.6%). The authors of Study 329 did not conduct analyses to see whether the aforementioned side effects occurred more commonly on drug vs. placebo.

Funny how they had time to dredge through every conceivable efficacy outcome but couldn't see whether the difference in severe adverse events was statistically significant.

One quote from the discussion section of the paper sums it all up:

There was no significant efficacy difference between paroxetine and placebo on the two primary outcomes or six secondary outcomes in the original protocol. At least 19 additional outcomes were tested. Study 329 was positive on 4 of 27 known outcomes (15%). There was a significantly higher rate of SAEs with paroxetine than with placebo. Consequently, study 329 was negative for efficacy and positive forharm.

But the authors concluded infamously that "Paroxetine is generally well-tolerated and effective for major depression in adolescents."

Enter Ghostwriters. Documentary evidence as shown on indicated that the first draft of the study was ghostwritten. This leaves two roles for the so-called academic authors of this paper:

They were willing co-conspirators who committed scientific fraud.

They were dupes, who dishonestly represented that they had a major role in the analysis of data and writing of the study, when in fact GSK operatives were working behind the scenes to manufacture these dubious results.

Remember, this study was published in 2001, and there has still been no apology for the fictional portrayal of its results, wherein a drug that was ineffective and unsafe was portrayed as safe and effective. Physicians who saw the authorship line likely thought "Gee, this is a who's who among academic child psychiatrists -- I can trust that they provided some oversight to make sure GSK didn't twist the results." But they were wrong.

By the way, Martin Keller, the lead "independent academic" author of this tragedy of a study said, when asked about what it means to be a key opinion leader in psychiatry:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

So is completely misrepresenting the data from a study "honorable"? Is Keller's opinion "worth considering?" As you know if you've read this blog for long, such behavior is, sadly, not a fluke occurrence. Many others who should be providing leadership are leading us on a race to the scientific and ethical bottom. What will Brown University, home of Keller, do? Universities don't seem to care at all about scientific fraud, provided that the perpetrators of bad science are bringing home the bacon.

Not one of the "key opinion leaders" who signed on as an author to this study has said, "Yep, I screwed up. I didn't see the data and I was a dupe." Nobody. Sure, I don't expect that every author of every publication can vouch for the data with 100% certainty. I understand that. But shouldn't the lead authorbe taking some accountability?

This is a Fluke (?)Some may be saying: "But this is just a fluke occurrence." Is it? I've seen much evidence that data are often selectively reported in a manner like this -- looks like (sadly) it takes a lawsuit for anyone to get a whiff of the bastardization of $science that passes for research these days. If GSK had not been sued, nobody would have ever known that the published data from Study 329 were negative. A reasonably educated person could see that the writeup of the study was a real pimp job -- lots of selling the product based on flimsy evidence, but nobody would have seen the extent of the fraud. Apparently lawyers need to police scientists because scientists are incapable of playing by some very basic rules of science.

See for Yourself. Documents upon which the latest Jureidini et al. paper are based can be found here. Happy digging.

7 comments:

The process of grinding out multiple post hoc secondary analyses that are then cherry-picked to suit the marketing message is called HARKing -- Hypothesizing After the Results Are Known. Study 329 is now in the HARKing hall of fame, er, infamy.

I think the 329 write-up is one of the great works of literature to emerge in the last twenty years! When I was looking at it, I was entertained greatly by the fact that the only authors to have anything to do with the Study were SKB's Chief Statistician (Rosemary Oakes), and the manager of the Paxil Phase 4 trials (James McCafferty). I imagine that it's perfectly normal for employees to write articles about their Company's products, but to a layman, such as myself, it looks decidedly odd, especially when McCafferty started coaching the ghostwriter, Sally Laden, on the way that she should be presenting the side effect commentary!

Presently, for the treatment of depression and other what some claim are mental disorders, some of which are questionable, selective serotonin reuptake inhibitors are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Cymbalta and Effexor

Some Definitions:

Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected with limited scientific evidence.Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression.

And depression is only one of those mood disorders, yet possibly the most devastating one. An accurate diagnosis of these mood conditions lack complete accuracy as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires. There is no objective diagnostic testing for depression. Yet the diagnosis of depression in patients has increased quite a bit over the decades.

Several decades ago, less than 1 percent of the U.S. population were thought to have depression. Today, it is believed that about 15 percent of the population have depression at some time in their lives. Why this great increase in the growth of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for support of their psychotropic meds, as this industry clearly desires market growth of these products, as this objective is part of their nature. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders that may be suspected by a doctor.

Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is being promoted for treatment for menopause. The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children.

Furthermore, these meds have received additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. Social phobia is a personality trait, in my opinion, which has been called shyness, which probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations as well with the different SSRIs or SRNIs. So the market continues to grow with these meds. Yet, it is believed that these meds are effective in only about half of those who take them. The makers of such meds create such conditions besides depression for additional utilization of these types of medications, and are active and have been active in forming symbiotic relationships with related groups, such as providing financial support for screenings for the indicated conditions of their meds- screening of children and adolescents in particular, I understand.

More concerning, however, is the adverse effects associated with these types of meds, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, among others. While most are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention. The reasons for this attention are the off-label use of these meds in this population, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, including the decreased efficacy of SSRIs in general, which is believed to be less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue some time ago for hiding such important information, for example, some time ago.And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits? Are adolescents depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It is observed in some who take such meds, but not all who take these meds.

Finally, if SSRIs are discontinued, withdrawals are brutal, and may be a catalyst for suicide in itself, as not only are these meds habit forming, but discontinuing these meds leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI. This occurs to some degree with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs.SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s mental issues where these types of meds are used, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered, but that is up to the discretion of the prescriber.

My name is Michael Smith and i would like to show you my personal experience with Paxil.

I am 40 years old. Have been on Paxil for 5 years now. Please be careful if coming off, i started to wean myself with out doctors help couldnt afford it. I went from 20 mgs to 10 mgs for a month, then 10 mgs to 5 mgs for a month. Because the 20 mgs were way to strong took 20 for 5 years and was always on edge. After about 1 month on 10 felt a little better. I stopped for 7 days completly and man did I feel like shit man I didn’t want to leave the house , shop! I just started back on 5 mgs to get it back in my system. Who know what is the right amount you have to be the test subject on yourself!

I have experienced some of these side effects-Headaches, tremors, emotional wreck, just the blah's when I 1st started takin wasnt bad, cause I also way taken klonopin.

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About Me

I'm an academic with a respectable amount of clinical experience and no drug industry funding. Given my lack of time, don't expect multiple daily updates. Certain things about clinical psychology, the drug industry, psychiatry, and academics drive me nuts, and you'll probably pick up on these pet peeves before long...